Human Herpesvirus 6 and Neuroinflammation

Reynaud, Joséphine M.; Horvat, Branka

doi:https://doi.org/10.5402/2013/834890

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Review Article | Open Access

Volume 2013 | Article ID 834890 | https://doi.org/10.5402/2013/834890

Human Herpesvirus 6 and Neuroinflammation

Joséphine M. Reynaud¹and Branka Horvat¹

Academic Editor: L. Margolis, B. Kim, M. Magnani

Received21 Jan 2013

Accepted13 Feb 2013

Published14 Mar 2013

Abstract

Human herpesvirus (HHV-) 6A and HHV-6B are two distinct β-herpesviruses which have been associated with various neurological diseases, including encephalitis, meningitis, epilepsy, and multiple sclerosis. Although the reactivation of both viruses is recognized as the cause of some neurological complications in conditions of immunosuppression, their involvement in neuroinflammatory diseases in immunocompetent people is still unclear, and the mechanisms involved have not been completely elucidated. Here, we review the available data providing evidence for the capacity of HHV-6A and -6B to infect the central nervous system and to induce proinflammatory responses by infected cells. We discuss the potential role of both viruses in neuroinflammatory pathologies and the mechanisms which could explain virus-induced neuropathogenesis.

1. Introduction

Human herpesvirus (HHV-) 6 was first isolated in 1986 by Salahuddin and colleagues [1]. This enveloped DNA virus belongs to the β-herpesvirus family and, together with its closest homologue HHV-7, forms the roseoloviruses subfamily. HHV-6 is widely spread in the population (seroprevalence > 90%) and can establish a persistent and most often asymptomatic infection in humans. Based on genetic, epidemiological, and functional features, the numerous isolated strains of HHV-6 were initially separated into two variants, HHV-6A and HHV-6B, which have recently been recognized as two distinct viruses. HHV-6A and -6B share an overall sequence identity of 90%, and several open reading frames are present in only one of the two viruses [2]. Primary infection with HHV-6B generally happens before the age of two; the virus is transmitted through saliva and close contacts with parents [3] and provokes exanthem subitum (or roseola), a benign febrile illness with skin rash. HHV-6A infection is thought to happen later in life and was not yet clearly identified as the causative agent for any disease.

To date, the only identified cellular receptor for both HHV-6A and -6B is the complement-regulatory transmembrane protein CD46 [4]. This protein is ubiquitously expressed in humans, allowing the viruses to infect a wide range of cells and tissues, including cells from the central nervous system (CNS). Both viruses have a high tropism towards T cells, which are the best virus producers in vitro, and can establish a persistent infection in different tissues, including the salivary glands (for HHV-6B only) and peripheral lymphocytes.

In immunocompromised patients, HHV-6A and -6B often reactivate and can provoke neurological pathologies. Moreover, many clinical studies have reported an association between HHV-6A and -6B and neuroinflammatory diseases, such as encephalitis or multiple sclerosis (MS), suggesting a role for both viruses in inflammatory processes. Indeed, although HHV-6A and -6B are generally considered as immunosuppressive agents, allowing them to evade the immune system, reports showing their proinflammatory properties are accumulating. Here, we review the available data providing evidence for HHV-6A and -6B infection in the human brain and their involvement in neurological diseases, and we discuss the potential mechanisms by which they could participate in neuroinflammation.

2. HHV-6A and HHV-6B Are Neurotropic Viruses

2.1. Evidence for the Presence of HHV-6A and -6B in the Brain

Although HHV-6 was first identified as a lymphotropic virus, it is now admitted that both HHV-6A and -B can also infect the brain. Indeed, several studies have reported the presence of HHV-6 DNA in different brain regions of healthy immunocompetent adults [5–11] as well as some viral transcripts, using in situ hybridization techniques [12]. However, in most of these studies, investigators failed to detect viral antigens, suggesting that HHV-6 may establish a latent infection in the brain in normal conditions. Overall, HHV-6B DNA was found more frequently in the brain than HHV-6A [7–9], in correlation with its higher prevalence, which indicates that both viruses have similar neuroinvasive properties. In contradiction, the analysis of the presence of HHV-6A and -6B DNA in the cerebrospinal fluid (CSF) of children with acute primary infection suggested that HHV-6A infection is more often restricted to the brain [13]. In some cases, both viruses can coexist in the brain, though their DNA was detected in different brain areas [9, 13]. Very little is known concerning the mechanisms of HHV-6 entry in the CNS. HHV-6B is thought to invade the brain and to establish persistent infection directly after primary infection [14]. Concerning HHV-6A, a recent study indicated that it might be able to travel through the olfactory pathway to reach the brain, thanks to its ability to infect specialized glial cells located in the nasal cavity [15].

2.2. Cell Tropism within the Human Brain

Histology analyses suggest that HHV-6A and -6B infect oligodendrocytes in vivo [7, 12], especially in case of productive infection (characterized by mRNA expression and production of viral proteins). In vitro experiments confirmed the capacity of the virus to infect oligodendroglial cell lines [16–18], as well as primary adult oligodendrocytes [19] and primary oligodendrocyte precursors, in which both HHV-6A and HHV-6B were able to induce syncytia formation, cell cycle arrest, and cell differentiation [20]. By histology analysis, Donati et al. found HHV-6 antigens in cells expressing the astrocyte marker glial fibrillary acidic protein (GFAP) in the brain of patients with temporal lobe epilepsy, indicating that HHV-6 can also infect astrocytes in vivo [21]. HHV-6A inoculation resulted in productive infection in primary fetal astrocytes [22–24] and induced apoptosis in both primary cells and astroglioma cell lines [17, 25] with syncytia formation (Figure 1). On the contrary, infection of astrocytes with HHV-6B seems to be less efficient, leading to decreasing viral DNA load and fewer morphological changes, which indicates that the two HHV-6 viruses may have different infection patterns within the brain. Fewer data concerning the infection of neurons and microglial cells are available; yet, some studies suggested that both cell types may be susceptible to HHV-6A and/or -6B infection in vitro [16, 17, 19, 24]. HHV-6A seems to be able to induce the formation of syncytia in neuroblastoma cell lines (Figure 1), and infected neurons were detected by immunostaining in patients who succumbed to HHV-6 encephalitis [26].

(a)

(b)

(c)

(d)

Both HHV-6A and -6B are then able to invade the central nervous system and to establish a persistent infection. However, HHV-6A seems to infect astrocytes and neurons more efficiently than HHV-6B, which may lead to the induction of different CNS pathologies.

3. Evidence for Proinflammatory Effects of HHV-6

HHV-6 was initially identified as an immunosuppressive virus. Primary infection with HHV-6B is indeed often associated with a decrease in leukocyte numbers [3], and both HHV-6A and -6B preferentially infect T lymphocytes in vivo and in vitro, reducing their proliferation [27–29] and inducing their apoptosis [30, 31]. Nevertheless, HHV-6A and -6B have also been demonstrated to exhibit proinflammatory properties in different contexts and have been suggested as potential agents in several inflammatory diseases, such as hepatitis [32], Sjögren’s syndrome [33, 34], rheumatoid arthritis [35, 36], systemic lupus erythematosus [35, 37], and more recently Hashimoto’s thyroiditis [38]. While these associations remain hypothetical, extensive in vitro studies provide evidence for HHV-6A and -6B proinflammatory effects on a variety of cell types and tissues (summarized in Table 1).

The effects of HHV-6A and -6B on the cytokine expression profile in different types of immune cells have been widely investigated. Some studies have suggested that both viruses can induce a Th2 profile in T cells through the inhibition of IL-12 secretion by dendritic cells (DCs) and macrophages [39, 40] and through the induction of IL-10 production by peripheral blood mononuclear cells (PBMCs) [41]. In contradiction, other reports have shown that HHV-6 infection upregulates the expression of proinflammatory cytokines, including IL-1β, TNFα, and IFNα in PBMC [42, 43], induces IL-18 and IFNγ receptor, and reduces IL-10 and IL-14 expression in T cells [44, 45], thus directing T cells towards a Th1 phenotype.

HHV-6A was also shown to exacerbate the cytotoxicity and IL-15 production in NK cells [46], as well as TNFα and IL-15 expression in monocytes [47, 48]. In plasmacytoid DC, HHV-6B was recently shown to induce type III IFN production, which has similar antiviral properties as type I IFN but had no effect on the Th1/Th2 balance [49].

In addition, studies on ex vivo cultures of lymphoid tissue showed that both HHV-6A and -6B can induce the secretion of chemokines in infected cells. Grivel et al. cultured freshly excised human tonsils and demonstrated that HHV-6A and -6B productive infection could be achieved, inducing an upregulation of CCL-5 and CCL-3 expression [50, 51]. Meeuwsen et al. performed a transcriptional microarray analysis on infected astrocytes and showed that HHV-6A infection increased the expression of many proinflammatory cytokines upon stimulation with TNFα, IL-1β, and IFNγ, including several chemokines (e.g., CCL-2, CCL-5, and CXCL-2) [45]. Moreover, HHV-6A was found to up-regulate the production of chemokines in primary endothelial cells [52, 53] and in a hepatoma cell line [54], indicating that the infection can promote the recruitment of leukocytes to different targeted tissues.

Altogether, these studies indicate that HHV-6A and -6B both have diverse proinflammatory effects on a variety of cell types. Although they could exhibit anti-inflammatory effects on some cell types, they are also able to increase the production of proinflammatory cytokines by some other cell types (Table 1) and to induce the development of a Th1 phenotype in T cells, thus eliciting the immune response. Moreover, they participate in the establishment of the inflammation in infected tissues by inducing the production of chemokines by resident cells. There is an apparent contradiction in the observed effects of HHV-6 infection, which include both the induction of immunosuppression and the promotion of inflammation. These differences may depend on the analyzed cell types or on infection kinetics representing different stages of infection and would require additional studies to be better understood.

4. HHV-6 and Neurological Diseases

HHV-6A and HHV-6B have both been directly or indirectly associated with neurological diseases [55–57], in cases of primary infection in immunocompetent young children, reactivation in otherwise healthy adults [3], or in immunosuppressed patients [58].

4.1. Infection in the “Immunocompetent” Population

HHV-6B was long ago conclusively identified as the etiologic agent for exanthem subitum (ES), a common infant febrile illness with skin rash [59]. Although ES is generally benign, it can be associated with various neurological complications, including convulsions, seizures, and encephalitis [60–62], often resulting in ataxia and epilepsy [63–66]. The most severe forms of encephalitis associated with ES can even lead to fatal outcome [67, 68].

In immunocompetent adults, evidence for the direct implication of HHV-6A or -6B in neurological diseases is more difficult to provide. Viral DNA loads in the serum and CSF, as well as IgM levels, are commonly used to detect HHV-6 infection. Based on these data, some cases of probable HHV-6-related encephalitis or meningoencephalitis have been reported in otherwise healthy adults and sometimes successfully treated with antiviral drugs [69–71]. Furthermore, studies of patients with encephalitis of unknown etiology strongly suggested that HHV-6 could be involved in disease establishment in certain cases [72–74].

4.2. Reactivation in Immunosuppressed Patients

As for other latent human herpesviruses, immunological defects are able to trigger HHV-6 reactivation from latency. Indeed, HHV-6A and -6B have been suggested to reactivate in immunocompromised patients, which received chemotherapy treatments or were diagnosed with AIDS. In hematopoietic stem cell transplant recipients especially, HHV-6 DNA (mostly -6B) was detected in the serum or PBMC in around 50% of the cases [58, 75, 76], indicating that viral reactivation has occurred. In several case reports, where no other possible cause was found, neurological complications in immunosuppressed people have been attributed to HHV-6 reactivation [56, 58]. Its involvement in encephalitis development was generally supported by the detection of viral DNA in the CSF and more rarely by the presence of viral proteins in affected areas of the brain at autopsy [26, 77, 78]. Moreover, several epidemiological studies have suggested a correlation between the risk of developing neurological symptoms and HHV-6 reactivation [79–81].

4.3. Association with Multiple Sclerosis

HHV-6 has long been cited as a potential candidate virus for the etiology of multiple sclerosis (MS). The importance of this inflammatory neurological disease, which represents the first cause of nontraumatic handicap in young adults, particularly inspired the research in this area. Abundant clinical studies have highlighted a correlation between MS and several parameters assessing for HHV-6 infection. For instance, the levels of HHV-6 DNA in the serum, which are characteristic of ongoing infection, are significantly increased in MS patients when compared to healthy donors or with patients with other diseases [82–85]. HHV-6 DNA was also detected at higher frequencies in the CSF and in the peripheral blood mononuclear cells of MS patients [82, 84, 86]. Moreover, the levels of HHV-6-specific IgG and IgM in the serum and in the CSF were reported to be higher in MS patients in several studies [83, 86, 87], although this phenomenon does not appear to be specific for HHV-6. Indeed, some groups have reported similar increases in the titers of antibodies against other viruses including Epstein-Barr virus or varicella-zoster virus. Soldan et al. also showed that lymphoproliferative responses against HHV-6 antigens were increased in MS patients [88]. The analysis of brain biopsies and postmortem tissues indicated that HHV-6 DNA was present more frequently in the brain of MS patients than in control brains, and that it was also more frequent in MS lesions than in normal areas of the same brains. Immunohistochemistry analyses confirmed the presence of viral proteins in oligodendrocytes and astrocytes in the brain from MS patients, with a higher frequency in demyelinating plaques [7, 12, 87, 89, 90]. Most interestingly, viral loads were detected more frequently, and levels of HHV-6-specific IgG were increased in MS patients experiencing disease exacerbation [84, 91–93], thus suggesting a correlation between HHV-6 infection and MS relapses.

As the distinction of HHV-6A and -6B as two different viruses was only recently adopted, many of the initial studies do not discriminate between the two variants. However, based on few reports, it appears that HHV-6A is found more frequently than -6B in the serum of MS patients [94]. Especially in case of active infection, Alvarez-Lafuente et al. have found only HHV-6A [92]. In contrast, in one study, intrathecal HHV-6B IgG levels were more abundant than HHV-6A IgG in MS patients, and only HHV-6B-specific IgM levels were found [95].

The potential association between HHV-6A and HHV-6B infection and MS has often been discussed and remains controversial. Some studies provided contradictory results [96–98], raising methodological and technical questions, especially concerning the choice of control groups and the immunological state of the included patients, who often receive immunosuppressive treatments, that may provoke latent herpesvirus reactivation by itself. Some studies have taken these matters into account and therefore provide solid data supporting the existence of a correlation between HHV-6 infection and MS pathology. Yet, whether HHV-6 infection is the etiologic cause, a factor for disease progression, or a consequence of MS remains unclear and would need further investigation.

5. Potential Mechanisms for HHV-6-Induced Neuroinflammation

Although the potential role of HHV-6A and -6B in MS has not been completely elucidated, both viruses have been conclusively involved in some cases of encephalitis in immunocompromised patients and in neurological complications of exanthem subitum. Several observations may provide explanations on how HHV-6 could trigger or participate in the establishment of neuroinflammation.

5.1. Molecular Mimicry

Among the mechanisms proposed for virus-induced autoimmunity, molecular mimicry is one of the most popular ones. Based on the similarity in peptide sequence between viral proteins and self-proteins, it has been postulated that viral infections could activate cross-reactive T cells, able to recognize both viral and self-antigens, which could then trigger an autoimmune response and cause tissue damage. Several studies suggest that such a mechanism could be involved in HHV-6-induced neuroinflammation. A first study reported that 15%–25% of HHV-6-specific T cell clones obtained from healthy donors or MS patients were cross-reactive to myelin basic protein (MBP), one of the autoantigens implicated in MS pathology [99]. In fact, MBP and the U24 protein from HHV-6 were later shown to share an identical amino acid sequence of 7 residues. Moreover, T cells directed against an MBP peptide also recognized an HHV-6 peptide, both peptides containing the identical sequence. Interestingly, cross-reactive cells were more frequent in MS patients than in controls [100]. These data were further confirmed by a more recent study, in which the presence of cross-reactive CD8⁺ cytotoxic T cells was found [101]. Altogether, these studies suggest that HHV-6 infection can activate T cell responses which can simultaneously be directed against myelin sheaths, thus strongly supporting the potential role for HHV-6 in autoimmune diseases affecting the CNS (Figure 2(a)).

Figure 2

Potential mechanisms for HHV-6-induced neuroinflammation. (a) Based on similarities between viral proteins and brain proteins, HHV-6A or -6B infection in the periphery could lead to the activation of cross-reactive T and B cells, able to recognize both viral antigens and brain antigens, and to the development of an autoimmune response directed to the brain (molecular mimicry). This would promote lymphocyte infiltration in the CNS, where they could have cytotoxic activities against resident cells, especially oligodendrocytes which express myelin antigens (1). Peripheral infection could also increase the inflammation by inducing IL-17 and inhibiting IL-10 production by T cells through CD46 binding (2). (b) Infection of astrocytes in the brain can lead to the release of proinflammatory cytokines and chemokines, which promote the infiltration of leukocytes expressing the corresponding chemokine receptor (3). Productive infection of CNS cells can result in the production of the viral chemokine U83, which can also attract leukocytes to the brain (4). Finally, infection of endothelial cells can induce the secretion of chemokines, thus attracting circulating leukocytes and facilitating their transmigration through the blood-brain barrier (5).

5.2. Infection of CNS Cells and Creation of a Proinflammatory Environment

As mentioned earlier, HHV-6A and HHV-6B are able to infect several CNS cell types, both in vitro and in vivo, and to trigger proinflammatory responses in a variety of infected cells. In particular, HHV-6A can infect primary astrocytes and induce the expression of several proinflammatory genes, especially when the cells have been pretreated with proinflammatory cytokines [45]. This suggests that HHV-6A could enhance the proinflammatory response of astrocytes, thus increasing leukocyte infiltration, in patients who already suffer from neuroinflammatory diseases (Figure 2(b)).

Recently, one study on dendritic cells demonstrated that HHV-6B can induce IFNλ-1 production via TLR-9 signaling [49]. Moreover, TLR-9 has been shown to be expressed in human astrocytes [102]. It is then likely that HHV-6A can alter astrocyte cytokine expression profile through TLR-9 signaling.

Other pattern recognition receptors, including TLR-2, -3, and -4, are expressed by human glial cells [102, 103] and neurons [104]. As HHV-6A and -6B are present in the brain of a subset of people, they may bind to these receptors upon reactivation and activate innate immune responses, thus promoting inflammation in the CNS.

Another consequence of HHV-6 infection of CNS cells could be the unmasking of autoantigens. HHV-6A was shown to induce cell death in oligodendrocytes and astrocytes either directly [25] or indirectly, via the production of soluble factors by productively infected T cells [17, 105]. Therefore, HHV-6A productive infection of CNS cells or the presence of productively infected lymphocytes in the brain could provoke the death of glial cells and release previously unrecognized self-antigens, thus initiating an autoimmune response directed to the brain.

5.3. Leukocyte Chemoattraction via Virokine Expression

The genome of HHV-6 encodes two G protein-coupled receptors, U22 and U51, similar to human chemokine receptors [106, 107] and one single chemokine-like protein, U83. The U83 gene from HHV-6B encodes a functionally active, highly specific agonist of the chemokine receptor CCR-2 [108, 109], which is expressed on monocytes and macrophages. Similarly, the U83 gene from HHV-6A encodes a homologous protein which can bind with high potency to several receptors, including CCR-1, -4, -5, and -8 [110], expressed by a variety of leukocytes. U83 is one of the few genes which are not present in the genome of Human Herpesvirus 7 (HHV-7), the closest homologue of HHV-6A and -6B. Interestingly, this other roseolovirus has not yet been associated with neuroinflammatory diseases.

Therefore, the productive infection of resident cells by both HHV-6A and -6B and the production of the U83 protein in the brain could then promote leukocyte infiltration in the CNS by chemoattraction (Figure 2(b)).

5.4. Infection of Endothelial Cells and Recruitment of Immune Cells to the CNS

Several studies have shown that HHV-6A can infect endothelial cells obtained from different organs [53, 111], and that infection induces the production of proinflammatory chemokines, such as CCL-5, CCL-2, and CXCL-8 [52, 53]. HHV-6A might then be able to infect endothelial cells of the brain vessels and, by increasing CCL-5 secretion, could potentially attract leukocytes to the blood-brain barrier. Moreover, a study reported that, in the context of liver transplantation, HHV-6 infection was correlated with overexpression of cell adhesion molecules, such as ICAM-1 and VCAM-1 in the vascular endothelium, and increased number of infiltrating lymphoid cells expressing their ligands, LFA-1 and VLA-4 [112]. Therefore, HHV-6 could potentially induce similar upregulation of cell adhesion proteins expression in CNS endothelial cells, thus increasing the blood-brain barrier permeability and facilitating the transfer of autoreactive lymphocytes in the brain (Figure 2(b)).

5.5. CD46 Engagement

The transmembrane protein CD46 is the only known entry receptor for both HHV-6A and -6B entry. This complement regulatory protein also plays an important role in the adaptive immune response as it can modulate T cell responses depending on which cytoplasmic tail is expressed [113] and can induce CD4⁺ T cells toward a Tr1 phenotype, with high IL-10 production [114]. One could then hypothesize that HHV-6A and -6B, by binding to their receptor, could modulate its functions. In support to this theory, a clinical study indicated that increase in HHV-6 viral load was correlated to enhanced CD46 expression in MS patients [115], and several alterations in CD46 functions were described; the CD46-induced IL-10 secretion by T cells was strongly decreased [116], whereas the CD46-dependant IL-23 production by DC and IL-17 expression by T cells were enhanced [117, 118]. This suggests that HHV-6 could participate in neuroinflammation in the context of MS, by promoting inflammatory processes through CD46 binding (Figure 2(a)).

5.6. Interaction with Other Infectious Agents

In the field of MS, many different genetic and environmental factors have been proposed as potential etiological agents. Yet, if considered separately, none of these candidates could be directly linked to the onset of the disease. Therefore, efforts are now focusing on combinations of factors, including both exogenous agents, such as living conditions or viral and bacterial infections, and endogenous factors, like genetic predispositions. One good example of these potential combinations is the interaction between herpesvirus infections and human endogenous retroviruses (HERVs) [119]. HERVs, which represent around 8% of the human genome, have been related to MS pathology since fully mature virions were isolated from leptomeningeal cells of an MS patient [120]. These viruses, and especially their envelope proteins, have strong inflammatory properties [121, 122]. HHV-6 infection seems to have direct transactivating properties on HERV, as it is able to increase their reverse transcriptase activity [123] and to stimulate the transcription of envelope genes [124, 125]. HHV-6 infection could then increase neuroinflammation by inducing HERV proteins, thus linking exogenous infections to endogenous factors.

6. Conclusion

HHV-6A and HHV-6B both exhibit neuroinvasive and proinflammatory properties. Moreover, both viruses are closely associated with neurological diseases involving inflammatory processes, which strongly supports the hypothesis that they can induce neuroinflammation.

The rare cases of encephalitis following primary HHV-6B infection, in which the virus is the only possible pathogenic cause of disease, provide evidence that HHV-6B has the ability to trigger inflammation in the brain. Whether this is a direct or indirect consequence of viral infection and whether the virus can induce such complications alone or in synergy with other factors remain to be clarified.

However, in other contexts, it is still difficult to bring solid proof of a decisive role for either HHV-6A or HHV-6B in the establishment of neuroinflammatory diseases. As HHV-6A appears to be more neurotropic and was more closely associated with multiple sclerosis, it may have more important implication in neurological diseases in adults. Yet, further investigations are still needed to better understand how these two viruses may participate in neuroinflammatory processes. The development of new tools, such as more complex in vitro systems or novel animal models in monkeys and humanized mice, could be of great help for the research in this field.

Acknowledgments

The work was supported by INSERM and ARSEP, and J. M. Reynaud was supported by a doctoral fellowship from the French ministry of research.

References

S. Z. Salahuddin, D. V. Ablashi, P. D. Markham et al., “Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders,” Science, vol. 234, no. 4776, pp. 596–601, 1986.
View at: Google Scholar
G. Dominguez, T. R. Dambaugh, F. R. Stamey, S. Dewhurst, N. Inoue, and P. E. Pellett, “Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A,” Journal of Virology, vol. 73, no. 10, pp. 8040–8052, 1999.
View at: Google Scholar
K. N. Ward, “The natural history and laboratory diagnosis of human herpesviruses-6 and -7 infections in the immunocompetent,” Journal of Clinical Virology, vol. 32, no. 3, pp. 183–193, 2005.
View at: Google Scholar
F. Santoro, P. E. Kennedy, G. Locatelli, M. S. Malnati, E. A. Berger, and P. Lusso, “CD46 is a cellular receptor for human herpesvirus 6,” Cell, vol. 99, no. 7, pp. 817–827, 1999.
View at: Google Scholar
M. Luppi, P. Barozzi, A. Maiorana, R. Marasca, and G. Torelli, “Human herpesvirus 6 infection in normal human brain tissue,” Journal of Infectious Diseases, vol. 169, no. 4, pp. 943–944, 1994.
View at: Google Scholar
M. Luppi, P. Barozzi, A. Maiorana et al., “Human herpesvirus-6: a survey of presence and distribution of genomic sequences in normal brain and neuroglial tumors,” Journal of Medical Virology, vol. 47, no. 1, pp. 105–111, 1995.
View at: Publisher Site | Google Scholar
P. B. Challoner, K. T. Smith, J. D. Parker et al., “Plaque-associated expression of human herpesvirus 6 in multiple sclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 16, pp. 7440–7444, 1995.
View at: Google Scholar
P. K. Chan, H. K. Ng, M. Hui, M. Ip, J. L. Cheung, and A. F. Cheng, “Presence of human herpesviruses 6, 7, and 8 DNA sequences in normal brain tissue,” Journal of Medical Virology, vol. 59, no. 4, pp. 491–495, 1999.
View at: Google Scholar
P. K. Chan, H. K. Ng, M. Hui, and A. F. Cheng, “Prevalence and distribution of human herpesvirus 6 variants A and B in adult human brain,” Journal of Medical Virology, vol. 64, no. 1, pp. 42–46, 2001.
View at: Google Scholar
L. Cuomo, P. Trivedi, M. R. Cardillo et al., “Human herpesvirus 6 infection in neoplastic and normal brain tissue,” Journal of Medical Virology, vol. 63, no. 1, pp. 45–51, 2001.
View at: Google Scholar
J. Chi, B. Gu, C. Zhang et al., “Human herpesvirus 6 latent infection in patients with glioma,” The Journal of Infectious Diseases, vol. 206, no. 9, pp. 1394–1398, 2012.
View at: Google Scholar
M. L. Opsahl and P. G. E. Kennedy, “Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter,” Brain, vol. 128, no. part 3, pp. 516–527, 2005.
View at: Publisher Site | Google Scholar
C. B. Hall, M. T. Caserta, K. C. Schnabel et al., “Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A,” Clinical Infectious Diseases, vol. 26, no. 1, pp. 132–137, 1998.
View at: Google Scholar
M. T. Caserta, C. B. Hall, K. Schnabel et al., “Neuroinvasion and persistence of human herpesvirus 6 in children,” Journal of Infectious Diseases, vol. 170, no. 6, pp. 1586–1589, 1994.
View at: Google Scholar
E. Harberts, K. Yao, J. E. Wohler et al., “Human herpesvirus-6 entry into the central nervous system through the olfactory pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 33, pp. 13734–13739, 2011.
View at: Google Scholar
L. De Bolle, J. Van Loon, E. De Clercq, and L. Naesens, “Quantitative analysis of human herpesvirus 6 cell tropism,” Journal of Medical Virology, vol. 75, no. 1, pp. 76–85, 2005.
View at: Google Scholar
J. L. Gardell, P. Dazin, J. Islar, T. Menge, C. P. Genain, and P. H. Lalive, “Apoptotic effects of Human Herpesvirus-6A on glia and neurons as potential triggers for central nervous system autoimmunity,” Journal of Clinical Virology, vol. 37, supplement 1, pp. S11–S16, 2006.
View at: Publisher Site | Google Scholar
J. Ahlqvist, J. Fotheringham, N. Akhyani, K. Yao, A. Fogdell-Hahn, and S. Jacobson, “Differential tropism of human herpesvirus 6 (HHV-6) variants and induction of latency by HHV-6A in oligodendrocytes,” Journal of NeuroVirology, vol. 11, no. 4, pp. 384–394, 2005.
View at: Publisher Site | Google Scholar
A. V. Albright, E. Lavi, J. B. Black, S. Goldberg, M. J. O’Connor, and F. González-Scarano, “The effect of human herpesvirus-6 (HHV-6) on cultured human neural cells: oligodendrocytes and microglia,” Journal For Neurovirology, vol. 4, no. 5, pp. 486–494, 1998.
View at: Google Scholar
J. Dietrich, B. M. Blumberg, M. Roshal et al., “Infection with an endemic human herpesvirus disrupts critical glial precursor cell properties,” Journal of Neuroscience, vol. 24, no. 20, pp. 4875–4883, 2004.
View at: Publisher Site | Google Scholar
D. Donati, N. Akhyani, A. Fogdell-Hahn et al., “Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections,” Neurology, vol. 61, no. 10, pp. 1405–1411, 2003.
View at: Google Scholar
D. Donati, E. Martinelli, R. Cassiani-Ingoni et al., “Variant-specific tropism of human herpesvirus 6 in human astrocytes,” Journal of Virology, vol. 79, no. 15, pp. 9439–9448, 2005.
View at: Publisher Site | Google Scholar
J. He, M. McCarthy, Y. Zhou, B. Chandran, and C. Wood, “Infection of primary human fetal astrocytes by human herpesvirus 6,” Journal of Virology, vol. 70, no. 2, pp. 1296–1300, 1996.
View at: Google Scholar
L. De Filippis, C. Foglieni, S. Silva, A. L. Vescovi, P. Lusso, and M. S. Malnati, “Differentiated human neural stem cells: a new ex vivo model to study HHV-6 infection of the central nervous system,” Journal of Clinical Virology, vol. 37, supplement 1, pp. S27–32, 2006.
View at: Publisher Site | Google Scholar
B. Gu, G.-F. Zhang, L. Y. Li et al., “Human herpesvirus 6A induces apoptosis of primary human fetal astrocytes via both caspase-dependent and -independent pathways,” Journal of Virology, vol. 8, p. 530, 2011.
View at: Google Scholar
W. R. Drobyski, K. K. Knox, D. Majewski, and D. R. Carrigan, “Brief report: fatal encephalitis due to variant B human herpesvirus-6 infection in a bone marrow-transplant recipient,” The New England Journal of Medicine, vol. 330, no. 19, pp. 1356–1360, 1994.
View at: Publisher Site | Google Scholar
B. Øster, B. Bundgaard, and P. Höllsberg, “Human herpesvirus 6B induces cell cycle arrest concomitant with p53 phosphorylation and accumulation in T cells,” Journal of Virology, vol. 79, no. 3, pp. 1961–1965.
View at: Google Scholar
L. Li, B. Gu, F. Zhou et al., “Human herpesvirus 6 suppresses T cell proliferation through induction of cell cycle arrest in infected cells in the G2/M phase,” Journal of Virology, vol. 85, no. 13, pp. 6774–6783, 2011.
View at: Google Scholar
L. Flamand, J. Gosselin, I. Stefanescu, D. Ablashi, and J. Menezes, “Immunosuppressive effect of human herpesvirus 6 on T-cell functions: suppression of interleukin-2 synthesis and cell proliferation,” Blood, vol. 85, no. 5, pp. 1263–1271, 1995.
View at: Google Scholar
Y. Inoue, M. Yasukawa, and S. Fujita, “Induction of T-cell apoptosis by human herpesvirus 6,” Journal of Virology, vol. 71, no. 5, pp. 3751–3759, 1997.
View at: Google Scholar
M. Yasukawa, Y. Inoue, H. Ohminami, K. Terada, and S. Fujita, “Apoptosis of CD4⁺ T lymphocytes in human herpesvirus-6 infection,” Journal of General Virology, vol. 79, part 1, pp. 143–147, 1998.
View at: Google Scholar
L. Potenza, M. Luppi, P. Barozzi et al., “HHV-6A in syncytial giant-cell hepatitis,” The New England Journal of Medicine, vol. 359, no. 6, pp. 593–602, 2008.
View at: Publisher Site | Google Scholar
R. I. Fox, I. Saito, E. K. Chan et al., “Viral genomes in lymphomas of patients with Sjögren’s syndrome,” Journal of Autoimmunity, vol. 2, no. 4, pp. 449–455, 1989.
View at: Google Scholar
S. Ranger-Rogez, E. Vidal, F. Liozon, and F. Denis, “Primary Sjögren’s syndrome and antibodies to human herpesvirus type 6,” Clinical Infectious Diseases, vol. 19, pp. 1159–1160, 1994.
View at: Google Scholar
G. R. F. Krueger, C. Sander, A. Hoffmann, A. Barth, B. Koch, and M. Braun, “Isolation of human herpesvirus-6 (HHV-6) from patients with collagen vascular diseases,” In Vivo, vol. 5, no. 3, pp. 217–225, 1991.
View at: Google Scholar
R. Alvarez-Lafuente, B. Fernández-Gutiérrez, S. de Miguel et al., “Potential relationship between herpes viruses and rheumatoid arthritis: analysis with quantitative real time polymerase chain reaction,” Annals of the Rheumatic Diseases, vol. 64, no. 9, pp. 1357–1359, 2005.
View at: Google Scholar
F. Broccolo, F. Drago, S. Paolino et al., “Reactivation of human herpesvirus 6 (HHV-6) infection in patients with connective tissue diseases,” Journal of Clinical Virology, vol. 46, no. 1, pp. 43–46, 2009.
View at: Google Scholar
E. Caselli, M. C. Zatelli, R. Rizzo et al., “Virologic and immunologic evidence supporting an association between HHV-6 and Hashimoto’s thyroiditis,” PLoS Pathogens, vol. 8, no. 10, Article ID e1002951, 2012.
View at: Google Scholar
A. Smith, F. Santoro, G. Di Lullo, L. Dagna, A. Verani, and P. Lusso, “Selective suppression of IL-12 production by human herpesvirus 6,” Blood, vol. 102, no. 8, pp. 2877–2884, 2003.
View at: Publisher Site | Google Scholar
A. P. Smith, C. Paolucci, G. Di Lullo, S. E. Burastero, F. Santoro, and P. Lusso, “Viral replication-independent blockade of dendritic cell maturation and interleukin-12 production by human herpesvirus 6,” Journal of Virology, vol. 79, no. 5, pp. 2807–2813, 2005.
View at: Publisher Site | Google Scholar
A. Arena, M. C. Liberto, D. Iannello, A. B. Capozza, and A. Focà, “Altered cytokine production after human herpes virus type 6 infection,” New Microbiologica, vol. 22, no. 4, pp. 293–300, 1999.
View at: Google Scholar
L. Flamand, J. Gosselin, M. D'Addario et al., “Human herpesvirus 6 induces interleukin-1β and tumor necrosis factor alpha, but not interleukin-6, in peripheral blood mononuclear cell cultures,” Journal of Virology, vol. 65, no. 9, pp. 5105–5110, 1991.
View at: Google Scholar
H. Kikuta, A. Nakane, H. Lu, Y. Taguchi, T. Minagawa, and S. Matsumoto, “Interferon induction by human herpesvirus 6 in human mononuclear cells,” Journal of Infectious Diseases, vol. 162, no. 1, pp. 35–38, 1990.
View at: Google Scholar
M. Mayne, C. Cheadle, S. S. Soldan et al., “Gene expression profile of herpesvirus-infected T cells obtained using immunomicroarrays: induction of proinflammatory mechanisms,” Journal of Virology, vol. 75, no. 23, pp. 11641–11650, 2001.
View at: Publisher Site | Google Scholar
S. Meeuwsen, C. Persoon-Deen, M. Bsibsi et al., “Modulation of the cytokine network in human adult astrocytes by human herpesvirus-6A,” Journal of Neuroimmunology, vol. 164, no. 1-2, pp. 37–47, 2005.
View at: Publisher Site | Google Scholar
L. Flamand, I. Stefanescu, and J. Menezes, “Human herpesvirus-6 enhances natural killer cell cytotoxicity via IL-15,” Journal of Clinical Investigation, vol. 97, no. 6, pp. 1373–1381, 1996.
View at: Google Scholar
A. Arena, M. C. Liberto, A. B. Capozza, and A. Focà, “Productive HHV-6 infection in differentiated U937 cells: role of TNFα in regulation of HHV-6,” New Microbiologica, vol. 20, no. 1, pp. 13–20, 1997.
View at: Google Scholar
A. Arena, R. A. Merendino, L. Bonina, D. Iannello, G. Stassi, and P. Mastroeni, “Role of IL-15 on monocytic resistance to human herpesvirus 6 infection,” New Microbiologica, vol. 23, no. 2, pp. 105–112, 2000.
View at: Google Scholar
I. Nordström and K. Eriksson, “HHV-6B induces IFN-lambda1 responses in cord plasmacytoid dendritic cells through TLR9,” PLoS ONE, vol. 7, no. 6, Article ID e38683, 2012.
View at: Google Scholar
J. C. Grivel, Y. Ito, G. Fagà et al., “Suppression of CCR5- but not CXCR4-tropic HIV-1 in lymphoid tissue by human herpesvirus 6,” Nature Medicine, vol. 7, no. 11, pp. 1232–1235, 2001.
View at: Publisher Site | Google Scholar
J.-C. Grivel, F. Santoro, S. Chen et al., “Pathogenic effects of human herpesvirus 6 in human lymphoid tissue ex vivo,” Journal of Virology, vol. 77, no. 15, pp. 8280–8289, 2003.
View at: Google Scholar
A. Caruso, F. Favilli, A. Rotola et al., “Human herpesvirus-6 modulates RANTES production in primary human endothelial cell cultures,” Journal of Medical Virology, vol. 70, no. 3, pp. 451–458, 2003.
View at: Publisher Site | Google Scholar
A. Caruso, A. Rotola, M. Comar et al., “HHV-6 infects human aortic and heart microvascular endothelial cells, increasing their ability to secrete proinflammatory chemokines,” Journal of Medical Virology, vol. 67, no. 4, pp. 528–533, 2002.
View at: Publisher Site | Google Scholar
R. Inagi, R. Guntapong, M. Nakao et al., “Human herpesvirus 6 induces IL-8 gene expression in human hepatoma cell line, Hep G2,” Journal of Medical Virology, vol. 49, no. 1, pp. 34–40, 1996.
View at: Google Scholar
D. K. Braun, G. Dominguez, and P. E. Pellett, “Human herpesvirus 6,” Clinical Microbiology Reviews, vol. 10, no. 3, pp. 521–567, 1997.
View at: Google Scholar
K. Yao, J. R. Crawford, A. L. Komaroff, D. V. Ablashi, and S. Jacobson, “Review part 2: human herpesvirus-6 in central nervous system diseases,” Journal of Medical Virology, vol. 82, no. 10, pp. 1669–1678, 2010.
View at: Google Scholar
H. Agut, “Deciphering the clinical impact of acute human herpesvirus 6 (HHV-6) infections,” Journal of Clinical Virology, vol. 52, no. 3, pp. 164–171, 2011.
View at: Google Scholar
D. M. Zerr, “Human herpesvirus 6 and central nervous system disease in hematopoietic cell transplantation,” Journal of Clinical Virology, vol. 37, upplement 1, pp. S52–S56, 2006.
View at: Google Scholar
K. Yamanishi, T. Okuno, K. Shiraki et al., “Identification of human herpesvirus-6 as a causal agent for exanthem subitum,” The Lancet, vol. 1, no. 8594, pp. 1065–1067, 1988.
View at: Google Scholar
Y. Asano, T. Yoshikawa, S. Suga et al., “Clinical features of infants with primary human herpesvirus 6 infection (exanthem subitum, roseola infantum),” Pediatrics, vol. 93, no. 1, pp. 104–108, 1994.
View at: Google Scholar
C. B. Hall, C. E. Long, K. C. Schnabel et al., “Human herpesvirus-6 infection in children—a prospective study of complications and reactivation,” The New England Journal of Medicine, vol. 331, no. 7, pp. 432–438, 1994.
View at: Publisher Site | Google Scholar
S. R. Barone, M. H. Kaplan, and L. R. Krilov, “Human herpesvirus-6 infection in children with first febrile seizures,” Journal of Pediatrics, vol. 127, no. 1, pp. 95–97, 1995.
View at: Google Scholar
Y. Asano, T. Yoshikawa, Y. Kajita et al., “Fatal encephalitis/encephalopathy in primary human herpesvirus-6 infection,” Archives of Disease in Childhood, vol. 67, no. 12, pp. 1484–1485, 1992.
View at: Google Scholar
T. Olli-Lähdesmäki, L. Haataja, R. Parkkola, M. Waris, N. Bleyzac, and O. Ruuskanen, “High-dose ganciclovir in HHV-6 encephalitis of an immunocompetent child,” Pediatric Neurology, vol. 43, no. 1, pp. 53–56, 2010.
View at: Publisher Site | Google Scholar
K. Yanagihara, K. Tanaka-Taya, Y. Itagaki et al., “Human herpesvirus 6 meningoencephalitis with sequelae,” Pediatric Infectious Disease Journal, vol. 14, no. 3, pp. 240–242, 1995.
View at: Google Scholar
K. B. Howell, K. Tiedemann, G. Haeusler et al., “Symptomatic generalized epilepsy after HHV6 posttransplant acute limbic encephalitis in children,” Epilepsia, vol. 53, no. 7, pp. e122–e126, 2012.
View at: Google Scholar
T. Yoshikawa, M. Ohashi, F. Miyake et al., “Exanthem subitum-associated encephalitis: nationwide survey in Japan,” Pediatric Neurology, vol. 41, no. 5, pp. 353–358, 2009.
View at: Publisher Site | Google Scholar
H. Matsumoto, D. Hatanaka, Y. Ogura, A. Chida, Y. Nakamura, and S. Nonoyama, “Severe human herpesvirus 6-associated encephalopathy in three children: analysis of cytokine profiles and the carnitine palmitoyltransferase 2 gene,” The Pediatric Infectious Disease Journal, vol. 30, no. 11, pp. 999–1001, 2011.
View at: Google Scholar
M. Patnaik and J. B. Peter, “Intrathecal synthesis of antibodies to human herpesvirus 6 early antigen in patients with meningitis/encephalitis,” Clinical Infectious Diseases, vol. 21, no. 3, pp. 715–716, 1995.
View at: Google Scholar
T. Birnbaum, C. S. Padovan, B. Sporer et al., “Severe meningoencephalitis caused by human herpesvirus 6 type B in an immunocompetent woman treated with ganciclovir,” Clinical Infectious Diseases, vol. 40, no. 6, pp. 887–889, 2005.
View at: Publisher Site | Google Scholar
E. Isaacson, C. A. Glaser, B. Forghani et al., “Evidence of human herpesvirus 6 infection in 4 immunocompetent patients with encephalitis,” Clinical Infectious Diseases, vol. 40, no. 6, pp. 890–893, 2005.
View at: Publisher Site | Google Scholar
J. A. McCullers, F. D. Lakeman, and R. J. Whitley, “Human herpesvirus 6 is associated with focal encephalitis,” Clinical Infectious Diseases, vol. 21, no. 3, pp. 571–576, 1995.
View at: Google Scholar
K. Yao, S. Honarmand, A. Espinosa, N. Akhyani, C. Glaser, and S. Jacobson, “Detection of human herpesvirus-6 in cerebrospinal fluid of patients with encephalitis,” Annals of Neurology, vol. 65, no. 3, pp. 257–267, 2009.
View at: Publisher Site | Google Scholar
N. P. Tavakoli, S. Nattanmai, R. Hull et al., “Detection and typing of human herpesvirus 6 by molecular methods in specimens from patients diagnosed with encephalitis or meningitis,” Journal of Clinical Microbiology, vol. 45, no. 12, pp. 3972–3978, 2007.
View at: Publisher Site | Google Scholar
T. Yoshikawa, Y. Asano, M. Ihira et al., “Human herpesvirus 6 viremia in bone marrow transplant recipients: clinical features and risk factors,” Journal of Infectious Diseases, vol. 185, no. 7, pp. 847–853, 2002.
View at: Publisher Site | Google Scholar
M. Ogata, “Human herpesvirus 6 in hematological malignancies,” Journal of Clinical and Experimental Hematopathology, vol. 49, no. 2, pp. 57–67, 2009.
View at: Google Scholar
J. Fotheringham, N. Akhyani, A. Vortmeyer et al., “Detection of active human herpesvirus-6 infection in the brain: correlation with polymerase chain reaction detection in cerebrospinal fluid,” Journal of Infectious Diseases, vol. 195, no. 3, pp. 450–454, 2007.
View at: Google Scholar
F. Forest, S. Duband, S. Pillet et al., “Lethal human herpesvirus-6 encephalitis after cord blood transplant,” Transplant Infectious Disease, vol. 13, no. 6, pp. 646–649, 2011.
View at: Google Scholar
P. Ljungman, F. Z. Wang, D. A. Clark et al., “High levels of human herpesvirus 6 DNA in peripheral blood leucocytes are correlated to platelet engraftment and disease in allogeneic stem cell transplant patients,” British Journal of Haematology, vol. 111, no. 3, pp. 774–781, 2000.
View at: Publisher Site | Google Scholar
D. M. Zerr, T. A. Gooley, L. Yeung et al., “Human herpesvirus 6 reactivation and encephalitis in allogeneic bone marrow transplant recipients,” Clinical Infectious Diseases, vol. 33, no. 6, pp. 763–771, 2001.
View at: Publisher Site | Google Scholar
M. Ogata, H. Kikuchi, T. Satou et al., “Human herpesvirus 6 DNA in plasma after allogeneic stem cell transplantation: incidence and clinical significance,” Journal of Infectious Diseases, vol. 193, no. 1, pp. 68–79, 2006.
View at: Publisher Site | Google Scholar
F. Wilborn, C. A. Schmidt, V. Brinkmann, K. Jendroska, H. Oettle, and W. Siegert, “A potential role for human herpesvirus type 6 in nervous system disease,” Journal of Neuroimmunology, vol. 49, no. 1-2, pp. 213–214, 1994.
View at: Publisher Site | Google Scholar
S. S. Soldan, R. Berti, N. Salem et al., “Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA,” Nature Medicine, vol. 3, no. 12, pp. 1394–1397, 1997.
View at: Publisher Site | Google Scholar
S. Chapenko, A. Millers, Z. Nora, I. Logina, R. Kukaine, and M. Murovska, “Correlation between HHV-6 reactivation and multiple sclerosis disease activity,” Journal of Medical Virology, vol. 69, no. 1, pp. 111–117, 2003.
View at: Google Scholar
M. Garcia-Montojo, A. Martinez, V. De Las Heras et al., “Herpesvirus active replication in multiple sclerosis: a genetic control?” Journal of the Neurological Sciences, vol. 311, no. 1-2, pp. 98–102, 2011.
View at: Google Scholar
D. V. Ablashi, W. Lapps, M. Kaplan, J. E. Whitman, J. R. Richert, and G. R. Pearson, “Human Herpesvirus-6 (HHV-6) infection in multiple sclerosis: a preliminary report,” Multiple Sclerosis, vol. 4, no. 6, pp. 490–496, 1998.
View at: Google Scholar
J. E. Friedman, M. J. Lyons, G. Cu et al., “The association of the human herpesvirus-6 and MS,” Multiple Sclerosis, vol. 5, no. 5, pp. 355–362, 1999.
View at: Google Scholar
S. S. Soldan, T. P. Leist, K. N. Juhng, H. F. McFarland, and S. Jacobson, “Increased lymphoproliferative response to human herpesvirus type 6A variant in multiple sclerosis patients,” Annals of Neurology, vol. 47, no. 3, pp. 306–313, 2000.
View at: Google Scholar
V. J. Sanders, S. Felisan, A. Waddell, and W. W. Tourtellotte, “Detection of Herpesviridae in postmortem multiple sclerosis brain tissue and controls by polymerase chain reaction,” Journal of NeuroVirology, vol. 2, no. 4, pp. 249–258, 1996.
View at: Google Scholar
A. D. Goodman, D. J. Mock, J. M. Powers, J. V. Baker, and B. M. Blumberg, “Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions,” The Journal of Infectious Diseases, vol. 187, no. 9, pp. 1365–1376, 2003.
View at: Google Scholar
R. Berti, M. B. Brennan, S. S. Soldan et al., “Increased detection of serum HHV-6 DNA sequences during multiple sclerosis (MS) exacerbations and correlation with parameters of MS disease progression,” Journal of NeuroVirology, vol. 8, no. 3, pp. 250–256, 2002.
View at: Publisher Site | Google Scholar
R. Alvarez-Lafuente, V. De las Heras, M. Bartolomé, J. J. Picazo, and R. Arroyo, “Relapsing-remitting multiple sclerosis and human herpesvirus 6 active infection,” Archives of Neurology, vol. 61, no. 10, pp. 1523–1527, 2004.
View at: Google Scholar
S. Simpson Jr., B. Taylor, D. E. Dwyer et al., “Anti-HHV-6 IgG titer significantly predicts subsequent relapse risk in multiple sclerosis,” Multiple Sclerosis, vol. 18, no. 6, pp. 799–806, 2012.
View at: Google Scholar
N. Akhyani, R. Berti, M. B. Brennan et al., “Tissue distribution and variant characterization of human herpesvirus (HHV)-6: increased prevalence of HHV-6A in patients with multiple sclerosis,” Journal of Infectious Diseases, vol. 182, no. 5, pp. 1321–1325, 2000.
View at: Publisher Site | Google Scholar
J. Ongrádi, C. Rajda, C. L. Maródi, A. Csiszár, and L. Vecsei, “A pilot study on the antibodies to HHV-6 variants and HHV-7 in CSF of MS patients,” Journal For Neurovirology, vol. 5, no. 5, pp. 529–532, 1999.
View at: Google Scholar
A. M. Fillet, P. Lozeron, H. Agut et al., “HHV-6 and multiple sclerosis,” Nature Medicine, vol. 4, no. 5, pp. 537–538, 1998.
View at: Google Scholar
A. R. Coates and J. Bell, “HHV-6 and multiple sclerosis,” Nature Medicine, vol. 4, no. 5, pp. 537–538, 1998.
View at: Google Scholar
K. I. Voumvourakis, D. K. Kitsos, S. Tsiodras, G. Petrikkos, and E. Stamboulis, “Human herpesvirus 6 infection as a trigger of multiple sclerosis,” Mayo Clinic Proceedings, vol. 85, no. 11, pp. 1023–1030, 2010.
View at: Google Scholar
M. Cirone, L. Cuomo, C. Zompetta et al., “Human herpesvirus 6 and multiple sclerosis: a study of T cell cross-reactivity to viral and myelin basic protein antigens,” Journal of Medical Virology, vol. 68, no. 2, pp. 268–272, 2002.
View at: Publisher Site | Google Scholar
M. V. Tejada-Simon, Y. C. Q. Zang, J. Hong, V. M. Rivera, and J. Z. Zhang, “Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis,” Annals of Neurology, vol. 53, no. 2, pp. 189–197, 2003.
View at: Google Scholar
W. Cheng, Y. Ma, F. Gong et al., “Cross-reactivity of autoreactive T cells with MBP and viral antigens in patients with MS,” Frontiers in Bioscience, vol. 17, pp. 1648–1658, 2012.
View at: Google Scholar
C. S. Jack, N. Arbour, J. Manusow et al., “TLR signaling tailors innate immune responses in human microglia and astrocytes,” Journal of Immunology, vol. 175, no. 7, pp. 4320–4330, 2005.
View at: Google Scholar
M. Bsibsi, R. Ravid, D. Gveric, and J. M. Van Noort, “Broad expression of Toll-like receptors in the human central nervous system,” Journal of Neuropathology and Experimental Neurology, vol. 61, no. 11, pp. 1013–1021, 2002.
View at: Google Scholar
M. Lafon, F. Megret, M. Lafage, and C. Prehaud, “The innate immune facet of brain: human neurons express TLR-3 and sense viral dsRNA,” Journal of Molecular Neuroscience, vol. 29, no. 3, pp. 185–194, 2006.
View at: Publisher Site | Google Scholar
H. Kong, Q. Baerbig, L. Duncan, N. Shepel, and M. Mayne, “Human herpesvirus type 6 indirectly enhances oligodendrocyte cell death,” Journal of NeuroVirology, vol. 9, no. 5, pp. 539–550, 2003.
View at: Google Scholar
Y. Isegawa, Z. Ping, K. Nakano, N. Sugimoto, and K. Yamanishi, “Human herpesvirus 6 open reading frame U12 encodes a functional β- chemokine receptor,” Journal of Virology, vol. 72, no. 7, pp. 6104–6112, 1998.
View at: Google Scholar
R. S. B. Milne, C. Mattick, L. Nicholson, P. Devaraj, A. Alcami, and U. A. Gompels, “RANTES binding and down-regulation by a novel human herpesvirus-6 β chemokine receptor,” Journal of Immunology, vol. 164, no. 5, pp. 2396–2404, 2000.
View at: Google Scholar
P. Zou, Y. Isegawa, K. Nakano, M. Haque, Y. Horiguchi, and K. Yamanishi, “Human herpesvirus 6 open reading frame U83 encodes a functional chemokine,” Journal of Virology, vol. 73, no. 7, pp. 5926–5933, 1999.
View at: Google Scholar
H. R. Lüttichau, I. Clark-Lewis, P. Ø. Jensen, C. Moser, J. Gerstoft, and T. W. Schwartz, “A highly selective CCR2 chemokine agonist encoded by human herpesvirus 6,” The Journal of Biological Chemistry, vol. 278, no. 13, pp. 10928–10933, 2003.
View at: Google Scholar
D. R. Dewin, J. Catusse, and U. A. Gompels, “Identification and characterization of U83A viral chemokine, a broad and potent β-chemokine agonist for human CCRs with unique selectivity and inhibition by spliced isoform,” Journal of Immunology, vol. 176, no. 1, pp. 544–556, 2006.
View at: Google Scholar
C. A. Wu and J. D. Shanley, “Chronic infection of human umbilical vein endothelial cells by human herpesvirus-6,” Journal of General Virology, vol. 79, part 5, pp. 1247–1256, 1998.
View at: Google Scholar
I. Lautenschlager, M. Härmä, K. Höckerstedt, K. Linnavuori, R. Loginov, and E. Taskinen, “Human herpesvirus-6 infection is associated with adhesion molecule induction and lymphocyte infiltration in liver allografts,” Journal of Hepatology, vol. 37, no. 5, pp. 648–654, 2002.
View at: Google Scholar
J. C. Marie, A. L. Astier, P. Rivailler, C. Rabourdin-Combe, T. F. Wild, and B. Horvat, “Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell-induced inflammation,” Nature Immunology, vol. 3, no. 7, pp. 659–666, 2002.
View at: Publisher Site | Google Scholar
C. Kemper, A. C. Chan, J. M. Green, K. A. Brett, K. M. Murphy, and J. P. Atkinson, “Activation of human CD4⁺ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype,” Nature, vol. 421, no. 6921, pp. 388–392, 2003.
View at: Publisher Site | Google Scholar
R. Alvarez-Lafuente, M. Garcia-Montojo, V. De Las Heras, M. I. Dominguez-Mozo, M. Bartolome, and R. Arroyo, “CD46 expression and HHV-6 infection in patients with multiple sclerosis,” Acta Neurologica Scandinavica, vol. 120, no. 4, pp. 246–250, 2009.
View at: Publisher Site | Google Scholar
A. L. Astier, G. Meiffren, S. Freeman, and D. A. Hafler, “Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis,” Journal of Clinical Investigation, vol. 116, no. 12, pp. 3252–3257, 2006.
View at: Publisher Site | Google Scholar
A. Vaknin-Dembinsky, G. Murugaiyan, D. A. Hafler, A. L. Astier, and H. L. Weiner, “Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis,” Journal of Neuroimmunology, vol. 195, no. 1-2, pp. 140–145, 2008.
View at: Publisher Site | Google Scholar
K. Yao, J. Graham, Y. Akahata, U. Oh, and S. Jacobson, “Mechanism of neuroinflammation: enhanced cytotoxicity and IL-17 production via CD46 binding,” Journal of Hepatology, vol. 5, no. 3, pp. 469–478, 2010.
View at: Google Scholar
H. Perron, C. Bernard, J. B. Bertrand et al., “Endogenous retroviral genes, herpesviruses and gender in multiple sclerosis,” Journal of the Neurological Sciences, vol. 286, no. 1-2, pp. 65–72, 2009.
View at: Publisher Site | Google Scholar
H. Perron, J. A. Garson, F. Bedin et al., “Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 14, pp. 7583–7588, 1997.
View at: Publisher Site | Google Scholar
J. M. Antony, G. Van Marle, W. Opii et al., “Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination,” Nature Neuroscience, vol. 7, no. 10, pp. 1088–1095, 2004.
View at: Publisher Site | Google Scholar
A. Rolland, E. Jouvin-Marche, C. Viret, M. Faure, H. Perron, and P. N. Marche, “The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses,” Journal of Immunology, vol. 176, no. 12, pp. 7636–7644, 2006.
View at: Google Scholar
T. Brudek, P. Lühdorf, T. Christensen, H. J. Hansen, and A. Møller-Larsen, “Activation of endogenous retrovirus reverse transcriptase in multiple sclerosis patient lymphocytes by inactivated HSV-1, HHV-6 and VZV,” Journal of Neuroimmunology, vol. 187, no. 1-2, pp. 147–155, 2007.
View at: Google Scholar
A. K. Tai, J. Luka, D. Ablashi, and B. T. Huber, “HHV-6A infection induces expression of HERV-K18-encoded superantigen,” Journal of Clinical Virology, vol. 46, no. 1, pp. 47–48, 2009.
View at: Google Scholar
V. L. Turcanova, B. Bundgaard, and P. Höllsberg, “Human herpesvirus-6B induces expression of the human endogenous retrovirus K18-encoded superantigen,” Journal of Clinical Virology, vol. 46, no. 1, pp. 15–19, 2009.
View at: Google Scholar
C. Li, J. M. Goodrich, and X. Yang, “Interferon-gamma (IFN-γ) regulates production of IL-10 and IL-12 in human herpesvirus-6 (HHV-6)-infected monocyte/macrophage lineage,” Clinical and Experimental Immunology, vol. 109, no. 3, pp. 421–425, 1997.
View at: Google Scholar
T. Yoshikawa, Y. Asano, S. Akimoto et al., “Latent infection of human herpesvirus 6 in astrocytoma cell line and alteration of cytokine synthesis,” Journal of Medical Virology, vol. 66, no. 4, pp. 497–505, 2002.
View at: Publisher Site | Google Scholar

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